A New Hypothesis for Alzheimer’s : The Lipid Invasion Model

imhotep

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  • Mar 29, 2017
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    A new hypothesis for Alzheimer’s disease (AD) has been suggested—The Lipid Invasion Model.

    A recent paper argues that AD results from external influx of free fatty acids (FFAs) and lipid-rich lipoproteins into the brain, following disruption of the blood-brain barrier (BBB). The lipid invasion model explains how the influx of albumin-bound FFAs via a disrupted BBB induces bioenergetic changes and oxidative stress, stimulates microglia-driven neuroinflammation, and causes anterograde amnesia. It also explains how the influx of external lipoproteins, which are much larger and more lipid-rich, especially more cholesterol-rich, than those normally present in the brain, causes endosomal-lysosomal abnormalities and overproduction of the peptide amyloid-β (Aβ). This leads to the formation of amyloid plaques and neurofibrillary tangles, the most well-known hallmarks of AD. The lipid invasion model argues that a key role of the BBB is protecting the brain from external lipid access. It shows how the BBB can be damaged by excess Aβ, as well as by most other known risk factors for AD, including aging, apolipoprotein E4 (APOE4), and lifestyle factors such as hypertension, smoking, obesity, diabetes, chronic sleep deprivation, stress, and head injury.

    It suggests that this is the reason footballers and boxers are particularly at risk, and why the disease affects largely older people, because in both cases the blood brain barrier has been damaged or worn away.

    There are two types of Alzheimer's - the comparatively rare, inherited, early-onset form and the non-inherited, late-onset form, associated with aging. This latter form is becoming more and more common as people live longer but the current explanation known as the amyloid hypothesis relates more to the rarer inherited form.

    This explanation states that the disease is caused by excess levels of a protein called beta-amyloid. The Lipid Invasion Model supports this up to a point but argues that, in the late-onset form, beta-amyloid is just one of a number of factors that damage the blood brain barrier, allowing external lipids in.

    "A healthy blood brain barrier is incredibly important to how our brains function effectively. If the barrier gets damaged, as is the case with people who develop Alzheimer's, external lipids like cholesterol and fatty acids get a chance to pass through."

    "These external lipids are managed differently to those typically found within the brain. My theory proposes that these invading lipids are resulting in brain damage, like brain shrinkage, and development of amyloid plaques and 'tau tangles', which causes the behaviors characteristic of Alzheimer's, such as memory loss, sleep disorders and paranoia."

    Dr Jonathan Rudge, postdoctoral researcher at the University of Reading.